Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated tumour necrosis factor alpha (TNF-alpha) has been demonstrated in chronic cardiac failure (CCF) and may relate to severity of CCF and development of cachexia. We measured TNF receptor p55 in addition to TNF-alpha in an attempt to improve the detection rate of TNF-alpha activation, and simultaneously measured interleukin 6 (IL-6), interleukin 8 (IL-8) and C-reactive protein. Thirty-four patients with CCF and 24 control subjects were studied. Only TNF receptor p55 [6.95 (0.77-42.3) vs. 5.52 (1.50-13.36) ng mL-1 (median (range)] and IL-6 [0.335 (0-9.79) vs. 0(0-14.71) pg mL-1) were significantly elevated in patients compared with control subjects (both P < 0.05). All inflammatory markers were more frequently elevated in patients, but none correlated with any of the clinical parameters studied. Reasons for inflammatory marker elevation in CCF are uncertain, but future studies should measure the p55 TNF receptor and IL-6 in addition to TNF-alpha, to improve detection of cytokine activity.
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PMID:Cytokine profile in chronic cardiac failure. 895 9

We studied the effects of various phosphodiesterase (PDE) III inhibitors: amrinone, pimobendan and vesnarinone: a PDE IV inhibitor (Ro 20-1724) and a PDE V inhibitor (E-4021) on the production of cytokines which have been shown to depress myocardial function. Recently developed inotropic agents which inhibit PDE III activity have produced short-term hemodynamic benefits in patients with advanced heart failure, but long-term treatment with these agents has an adverse effect on survival. However, vesnarinone, which has been shown to improve survival dramatically, has an immunomodulating effect and inhibits the production of cytokines. Peripheral blood mononuclear cells obtained from healthy human subjects were stimulated with lipopolysaccharide and each PDE inhibitor was added. After 24 h of incubation, tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta) and IL-6 in the culture supernatants were measured by an enzyme-linked immunosorbent assay. All three PDE III inhibitors, amrinone, pimobendan and vesnarinone, inhibited TNF-alpha production, but vesnarinone's inhibitory effect was the most prominent. Amrinone and pimobendan enhanced IL-1 beta production, whereas vesnarinone had no effect. Vesnarinone inhibited IL-6 production and pimobendan slightly decreased IL-6 production, whereas amrinone had no significant effect on IL-6 production. The PDE IV inhibitor, Ro 20-1724, decreased the production of IL-1 beta and TNF-alpha and also tended to inhibit IL-6 production; its modulation of cytokine production was similar to the effects of vesnarinone. Because 8Br-cAMP or 8Br-cGMP did not suppress cytokine production, the modulating effects were not considered to result from an increase in cAMP or cGMP. Differential modulation of cytokine production may play a role in the therapeutic effect in heart failure patients who are treated with drugs that have PDE-inhibitory actions. It may be important to study whether the use of dual inhibitors of PDE III and PDE IV is therapeutically more useful for the treatment of heart failure due to their immunomodulating properties.
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PMID:Differential modulation of cytokine production by drugs: implications for therapy in heart failure. 900 65

Depression of myocardial contractility plays an important role in the development of heart failure; therefore, intensive interest and passion have been generated to develop cardiotonic agents to improve the contractile function of the failing heart. Inotropic agents that increase cyclic AMP, either by increasing its synthesis or reducing its degradation, exert dramatic short-term hemodynamic benefits, but these acute effects cannot be extrapolated into long-term improvement of the clinical outcome in patients with advanced heart failure. Administration of these agents to an energy-starved failing heart would be expected to increase myocardial energy use and could accelerate disease progression. The role of digitalis in the management of heart failure has been controversial, but ironically the drug has now been proved to favorably affect the neurohormonal disorders and its reevaluation is now being intensively investigated. More recently, attention has been focused on other inotropic agents that have a complex and diversified mechanism. Recent clinical studies have demonstrated that they are potentially useful in the long-term treatment of heart failure patients. These agents have some phosphodiesterase-inhibitory action but also possess additional effects, including acting as cytokine inhibitors, immunomodulators, or calcium sensitizers. However, their therapeutic ratio is narrow and further studies are warranted to establish their optimal doses and their eventual status in the treatment of heart failure.
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PMID:Inotropic agents in the treatment of heart failure: despair or hope? 911 Jan 13

Myocarditis is an inflammatory disorder of the heart muscle, and is often underdiagnosed in clinical practice. It presents more dramatically in the young with acute heart failure and more insidiously in adults with chronic dilated cardiomyopathy. The etiology is most often viral in North America, with a wide spectrum of natural history. The majority of patients recover spontaneously, but those with persistent ventricular dysfunction face a 20% one-year mortality. Myocarditis initiates as viral disease, and molecular techniques have confirmed viral persistence. The immune response follows as a two-edged sword-both inadequate and excessive immune responses lead to disease. Finally, the myocyte is the target of the above processes, and expresses molecular, cytokine and vascular changes that lead to dilated cardiomyopathy and heart failure. The gold standard for diagnosis still relies on the overly strict Dallas criteria for evaluating myocardial biopsies. Molecular techniques are playing an increasingly important role in both diagnosis and prognosis. Clinical suspicion is still the key towards an early diagnosis. Treatment must be early and persistent-generally supportive initially, with immunosuppression now playing a secondary role in temporizing those with exuberant immune response. Newer treatments for dilated cardiomyopathy such as amlodipine and carvedilol are equally appropriate for postmyocarditis patients. Future treatment may involve specific biological agents, immune therapy, antiviral strategies and molecular gene therapy.
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PMID:Viral myocarditis: balance between viral infection and immune response. 919 84

The pathogenesis of viral myocarditis has not been clarified yet especially in the subacute and chronic stages. Recent reports have shown that myocarditis may be caused by autoimmune reactions. Autoantigens and autoantibodies have recently been reported in myocarditis and cardiomyopathy, and most of them may be induced by the cross-reaction between virus and cardiac tissue, molecular mimicry, or by the destruction of immune tolerance. However it is not clear how autoimmune reactions affect viral myocarditis. We have reported that cytokines are increased in the blood of patients with myocarditis and cardiomyopathy. Many kinds of cytokines modulate viral myocarditis in different ways in murine models. Nitric oxide is also recognized as an important factor in viral myocarditis. We have reported that drugs for heart failure modulate cytokine production. Classifying drugs from this point of view may be helpful for developing new therapeutic strategy for patients with myocarditis and cardiomyopathy.
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PMID:[Viral myocarditis and autoimmunity]. 920 Sep 39

The pathogenesis of heart failure is determined by the ventricular and vascular responses to myocellular injury. Experimental and clinical studies suggest that the vascular endothelium may play an important role in modulating progression of ventricular and vascular remodeling in heart failure. Endothelial cell dysfunction has been described in the coronary and skeletal muscle circulations of patients with heart failure and appears to be characterized by decreased endothelial synthesis of nitric oxide and increased production of endothelin-1. The pathogenesis of endothelial dysfunction in heart failure is unknown, but may be related to increased oxidative stress, abnormal regional flow conditions, and cytokine and neurohormonal activation. The specific role of endothelial dysfunction in the pathogenesis of heart failure remains to be determined. If endothelial dysfunction does contribute to progression of disease in early heart failure, specific therapies to enhance endothelial dysfunction may improve long-term morbidity and mortality.
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PMID:Mechanisms and implications of endothelial dysfunction in congestive heart failure. 924 83

Cytokines are proteins with pleiotropic biological effects, but the pathophysiologic role of cytokine inhibitors in advanced cardiac disease remains unclear. We assessed the levels of tumor necrosis factor (TNF)-alpha and its soluble receptors I (sTNF-RI) and II (sTNF-RII), soluble interleukin-1 receptor antagonist (sIL-1 Ra), and interleukin-6 soluble receptor (IL-6 sR) in sera from 11 patients with severe chronic congestive heart failure (mean left ventricular ejection fraction 19 +/- 6%; mean symptom-limited oxygen consumption 13 +/- 4 ml/min per kg) and 11 healthy volunteers. The serum concentrations of TNF, sTNF-RI, and sIL-1 Ra, but not of sTNF-RII and IL-6 sR, were significantly increased in heart failure patients. Importantly, their symptom-limited oxygen consumption was strongly associated with both sTNF-RI (R = -0.68, p = 0.04) and sIL-1 Ra (R = -0.77, p = 0.01). These results suggest that cytokine inhibitors from different receptor families may be involved in functional disability, a characteristic feature in patients with severe congestive heart failure. Understanding the response of cytokine inhibitors to heart failure might have therapeutic value as interventions against cytokines become available.
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PMID:Cytokine inhibitors in patients with heart failure and impaired functional capacity. 929 4

Cytokines have been associated with the pathogenesis of acute coronary syndromes and chronic heart failure (CHF), which are both associated with cardiomyocyte loss. In CHF, increased serum concentrations of proinflammatory cytokines, including tumour necrosis factor alpha (TNF-alpha) and also soluble TNF receptor have been found. Both TNF and Fas-ligand have been able to induce programmed cell death (apoptosis) of cardiomyocytes in various experimental studies. In ischaemic conditions of the heart, increased serum levels of soluble Fas receptor have been found. The proinflammatory cytokines interleukin 1 (IL-1), IL-2 and interferon-gamma can induce TNF production from target cells, including myocytes. TNF and some other cytokines are able to induce nitric oxide production, which depresses cardiac function and can induce apoptosis. However, anti-inflammatory cytokines such as IL-10, IL-4 and IL-13, secreted by T-helper type 2 lymphocytes and other cells, inhibit the production of proinflammatory cytokines. Preliminary studies suggest that cardiotrophin-1, produced by cardiomyocytes, is able to inhibit cytokine-induced cardiomyocyte apoptosis in vitro. As growth hormone is able to inhibit the production of proinflammatory cytokines in many cell types, it may also play an important role in the regulation of apoptosis induced by these cytokines. When the cytokine-induced pathways leading to altered gene expression of cardiomyocytes are understood, this knowledge may aid in the development of drugs that prevent progressive cardiomyocyte loss, in particular by inhibiting cytokine-induced apoptosis.
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PMID:Cytokines and cardiomyocyte death. 937 93

Vesnarinone is a new and novel inotropic drug that has unique and complex mechanisms of action. It inhibits phosphodiesterase, thereby leading to increased intracellular calcium, and also affects numerous myocardial ion channels, resulting in the prolongation of the opening time of sodium channels and the decrease in the delayed outward and inward rectifying potassium current. In vitro, it has also demonstrated significant effects on cytokine production, which may account for some of its observed clinical benefits. Hemodynamic studies in humans with congestive heart failure reveal that vesnarinone can improve ventricular function. Placebo-controlled studies in large numbers of patients with heart failure have suggested a morbidity and mortality benefit with a 60 mg daily dose. There is increased mortality with vesnarinone at the 120 mg daily dose, however, suggesting a narrow therapeutic window for the drug. Its predominant toxic side effect is a 2% incidence of reversible neutropenia.
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PMID:Vesnarinone: a new inotropic agent for treating congestive heart failure. 942 Jun 57

Cytokines are being increasingly recognized as important factors in the pathogenesis and pathophysiology of heart failure. Elevated levels of circulating cytokines have been reported in patients with heart failure, and various cytokines have been shown to depress myocardial contractility in vitro and in vivo. We have recently compared the effects on cytokine production of drugs for therapy of heart failure that have different effects on survival. Amrinone, pimobendan and vesnarinone, phosphodiesterase III inhibitors that have been shown to have short term haemodynamic benefits, inhibited TNF-alpha production. Differential modulation of the production of IL-1beta and IL-6 was observed; amrinone and pimobendan enhanced the production of IL-1beta, whereas vesnarinone did not. As inotropic agents differentially modulate cytokine production, these agents may interfere with induction of inducible nitric oxide (NO) synthase through an inhibition of cytokine formation. Although differential modulation of the production of NO by inotropic agents may explain their different effect in patients with heart failure, further study is necessary to reach this conclusion. We have shown that amlodipine increases the survival of mice with viral myocarditis and inhibits expression of inducible NO synthase and production of NO in vivo and in vitro. The therapeutic effect of amlodipine may in part result from inhibition of overproduction of NO. As we learn more about the pathophysiological and pathogenetic role of cytokines in heart failure, it should be possible to design better and more targeted pharmacological agents. Furthermore, the investigation of inotropic agents that are effective against the production of cytokines may help in the classification of these agents.
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PMID:The use of cytokine inhibitors. A new therapeutic insight into heart failure. 946 76


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